Early Disseminated Lyme Disease Causing False-Positive Serology for Primary Epstein-Barr Virus Infection: Report of 2 Cases

Abstract

False-positive serology for Lyme disease was reported in patients with acute infectious mononucleosis. Here we describe 2 patients with early disseminated Lyme disease who were misdiagnosed with infectious mononucleosis based on false-positive tests for primary Epstein-Barr virus infection.

False-positive serologic results for Lyme disease were previously reported in patients with acute infectious mononucleosis [1–3]. We report 2 cases of false-positive Epstein-Barr virus (EBV) serologies in early disseminated Lyme disease.

Both patients provided written informed consent and were enrolled in protocols approved by the institutional review board of the National Institute of Allergy and Infectious Diseases.

CASE REPORT 1

In late May, 1 week after hiking for 1 day in Virginia, a previously healthy 16-year-old male, resident of Maryland, developed 3 brief episodes of fever that lasted for <24 hours over a period of 18 days. He also complained of fatigue and myalgias during this period. After the third episode, he was evaluated by his primary care physician. The patient was not aware of a tick bite. His physical examination was unremarkable. He had no rash, arthritis, pharyngitis, lymphadenopathy, or hepatosplenomegaly. Serologies were ordered for mononucleosis and Lyme disease. Three days later, a diagnosis of acute infectious mononucleosis was made based on a positive viral capsid antigen (VCA) immunoglobulin M (IgM) (113 U/mL, negative <36). VCA immunoglobulin G (IgG) and Epstein-Barr antibody to nuclear antigen (EBNA) were negative. C-reactive protein was 36.6 mg/L (reference range, 0.0–4.9 mg/L). Complete blood count and differential, alanine aminotransferase, and aspartate aminotransferase were within normal limits. Lyme serology was pending. Seventeen days after the blood draw, he developed multiple erythematous rashes and right-sided peripheral facial nerve palsy. During the reevaluation, the results of the previously collected Lyme serologic tests were found to be positive. The C6 peptide enzyme-linked immunosorbent assay (ELISA) index was 6.02 (positive >1.09), confirmed by a positive IgM immunoblot. The IgG immunoblot was negative. The patient completed a 4-week course of doxycycline with full recovery. Follow-up laboratory testing 2 months after the initial testing confirmed recent Borrelia burgdorferi infection. The C6 peptide ELISA index was 8.37 and both IgG and IgM immunoblots were positive. Repeat VCA IgG, VCA IgM, and EBNA were negative, indicating that the initial VCA IgM was falsely positive.

CASE REPORT 2

In early June, a 65-year-old woman, resident of Maryland and an avid hiker, became acutely ill with fatigue, fever, myalgias, and headache. After 6 days, she saw her physician and was diagnosed with a viral illness. The next day, she noticed an asymptomatic, erythematous round skin lesion on her right leg, followed by multiple similar lesions on her trunk, back and arms, which ranged from 2 to 6 cm in diameter. Ten days into her illness, she returned to her doctor and serologies were sent for mononucleosis and Lyme disease. Complete blood count and differential, alkaline phosphatase, aspartate aminotransferase, and bilirubin levels were within normal limits. The next day, she developed pain at her right parascapular region, which would expand and become more intense over the succeeding days. Twelve days into her illness, she was informed that she tested positive for mononucleosis. The VCA IgM was 2.0 AI (negative <0.9), VCA IgG was >8.0 AI (negative <0.9), EBV early antigen IgG was 0.9 AI (negative <0.9), and EBNA IgG was >8.0 (negative <0.9). The next evening, she was told that her Lyme serology was positive and was prescribed doxycycline 100 mg every 12 hours for 21 days, which she started in the morning. That night, her right parascapular pain intensified, and she was seen at the emergency department. The evaluation for cardiovascular and pulmonary disease was negative. A monospot was positive. Lyme serologies were positive, with a positive ELISA and IgG and IgM immunoblots. The patient was given intravenous analgesia and discharged on oral analgesia with acetaminophen and hydrocodone. The fever resolved and the rashes started to fade, but her pain progressed. Nerve conduction studies and electromyogram showed a right upper trunk brachial plexopathy. The pain resolved and the weakness improved over the next 6 months. Three and a half years later, repeat VCA IgG and EBNA were positive, and VCA IgM was negative.

DISCUSSION

Here we present 2 cases where early manifestations of Lyme disease were initially misdiagnosed as acute EBV infection due to positive VCA IgM results. In the case of our first patient, who initially presented with nonspecific symptoms, the false-positive VCA IgM may have contributed to delayed diagnosis of Lyme disease. He later developed manifestations of early disseminated Lyme disease that prompted reevaluation and led to the correct diagnosis. While isolated VCA IgM may indicate early acute mononucleosis, the test can be nonspecific, especially when the likelihood of acute EBV infection is low [4]. As VCA IgG is typically detectable at clinical presentation, the absence of a positive VCA IgG test made the diagnosis of acute mononucleosis less likely. Immune activation with other pathogens can also result in a false-positive VCA IgM [5]. The second case, which presented with manifestations of early disseminated Lyme disease including multiple erythema migrans lesions and neurological involvement, was also initially incorrectly diagnosed with mononucleosis based on a positive VCA IgM. In this case, we cannot exclude that the positive VCA IgM could be due to subclinical EBV reactivation, which has little clinical relevance in immunocompetent individuals [6]. The interpretation of the positive result led to a misdiagnosis of acute primary EBV infection. The patient also had a positive monospot test. Heterophile antibody tests are known to have false positives due to acute infections, autoimmune diseases, and cancer [7].

Epstein-Barr virus infection is known to cause false-positive results in Lyme disease serologic testing, particularly IgM tests, and samples from patients with recent EBV infection are commonly part of the serum panel used to study antibody-based tests for Lyme disease [2, 3, 8, 9]. To our knowledge, this is the first time that the reverse situation is described.

Notes

Disclaimer. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Financial support. This work was supported by the Intramural Research Program of the National Institute of Mental Health and National Institute of Allergy and Infectious Diseases.

Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.